bims-miptne 2026-08-23 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–08–23
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Adenine nucleotide-dependent inhibition of permeability transition pore: adenine nucleotide translocase and other players.
NLRX1 emerges as the only observed essential regulator of the mPTP, challenging mPTP inhibition as a valid target of cardioprotection.
Targeting Mitochondrial Dysfunction in Acute Organophosphate Toxicity: A Preliminary Evaluation of Cyclosporine A.
Mitochondrial sensitivity to Ca2+-induced permeability transition in mouse liver exhibits time-of-day dependence.
Specialized cortical ER architecture modulates Ca2+ signaling dynamics.
Repression of ferroptotic cell death mediated antitumor immunity by mitochondrial calcium signaling.
Programmed cell death in kidney disease: integrated crosstalk among ferroptosis, pyroptosis, apoptosis, and cuproptosis.
Iron-responsive transcription factor SreA regulates calcium homeostasis independently of calcineurin-Crz1 pathway in Fusarium graminearum.

Biochim Biophys Acta Bioenerg. 2026 Aug 21. pii: S0005-2728(26)00024-1. [Epub ahead of print] 149604

Adenine nucleotide-dependent inhibition of permeability transition pore: adenine nucleotide translocase and other players.

Alexey G Kruglov, Anna B Nikiforova, Marina V Akulenko, Ekaterina S Kharechkina, Irina V Odinokova, Ekhson L Holmuhamedov.

  Changes in the level and the ratio of adenine nucleotides (AN) are a common consequence of ischemia, which can promote mitochondrial permeability transition pore (mPTP) opening and cell death upon reperfusion. However, the mechanism of AN-dependent mPTP inhibition is not entirely clear. Here we studied the effects of inorganic phosphate, Mg2+, as well as the inhibitors of adenylate translocase (ANT) and FoF1-ATP synthase (F-ATPase) on the AN-dependent mPTP suppression and AN turnover mediated by a short Ca2+-dependent mitochondrial carrier (SCaMC). Also, we indirectly assessed the contribution of Ca2+ buffering by AN to mPTP suppression. We found that, at near-physiologic concentrations, AN suppressed mPTP opening (swelling) and increased the Ca2+-retention capacity much stronger than the ANT inhibitor bongkrekic acid (BA). Inorganic phosphate (Pi) and Mg2+ modulated the protective effect of AN. In solution, AN were an incomparably weaker Ca2+ buffer than matrix Pi. AN preserved the capability to suppress mPTP opening in the presence of both BA and carboxyatractyloside (CATR). The sensitivity of AN-dependent mPTP suppression to CATR decreased with a decrease in the Pi level. Mg2+ and BA, in contrast to CATR, partially inhibited the SCaMC-mediated AN turnover. The analysis of these and the earlier obtained data allowed us to propose a new mechanism of AN-dependent mPTP suppression: the coordinated ANT- and SCaMC-mediated AN turnover, which fine-tunes the Pi, Ca2+, and H+ ratios in the matrix for efficient Ca2+ sequestration. The mechanism does not require ANT stabilization in any conformation, allosteric regulators, and the formation of AN-Ca2+-Pi complexes.

Keywords:  Adenine nucleotide; Bongkrekic acid; Permeability transition pore; Phosphate; Short calcium-dependent mitochondrial carrier (SCaMC); Translocase of adenine nucleotides (ANT)

DOI:  https://doi.org/10.1016/j.bbabio.2026.149604
Basic Res Cardiol. 2026 Aug 19.

NLRX1 emerges as the only observed essential regulator of the mPTP, challenging mPTP inhibition as a valid target of cardioprotection.

Kielen R Zuurbier, Coert J Zuurbier.

  The mitochondrial permeability transition pore (mPTP) opening is a phenomenon in which the inner mitochondrial membrane abruptly becomes permeable when matrix calcium reaches a critical threshold. Despite 5 decades of intensive research, no protein has been universally accepted as essential for mPTP opening, limiting mechanistic understanding and raising questions about the validity of mPTP-targeted strategies to mitigate cardiac ischemia-reperfusion (I/R) injury. Here, we discuss convergent findings from two independent laboratories identifying the innate immune receptor NLRX1 as an unexpected, essential requirement for mPTP activity. NLRX1 is the only NOD-like receptor (NLR) that is targeted to the mitochondrion. NLRX1 deficiency abolishes (1) calcium-induced mPTP opening, (2) cyclosporine A sensitivity of the pore, and (3) mitochondrial calcium release following cardiac I/R. To test whether loss of mPTP function aligns with loss of NLRX1 across evolution, we performed forward and reciprocal bioinformatic (Blastp) searches and found that species reported to lack an mPTP (e.g., Artemia franciscana and Drosophila melanogaster) also lack NLRX1, further supporting a mandatory role for NLRX1 in mPTP occurrence. Notably, NLRX1-deficient hearts can exhibit increased, rather than decreased, I/R injury at specific ischemia durations. This mirrors reports that deletion of established mPTP regulators (e.g., Ppif) may also worsen injury under defined conditions, consistent with context-dependent, potentially protective roles for transient mPTP activity (e.g., mitochondrial calcium release, PI3K/Akt signaling). In summary, we propose that NLRX1 is the only currently identified protein that is strictly required for mPTP opening, and that indiscriminate inhibition of the mPTP is unlikely to represent a universally effective cardioprotective strategy against I/R injury.

Keywords:  Cardioprotection; Innate immunity; Ischemia-reperfusion injury; Mitochondria; NLRX1; mPTP

DOI:  https://doi.org/10.1007/s00395-026-01204-6
J Med Toxicol. 2026 Aug 19.

Targeting Mitochondrial Dysfunction in Acute Organophosphate Toxicity: A Preliminary Evaluation of Cyclosporine A.

David H Jang, Jarelis Cabrera, Jonathan Starr, Abigail Insana, Angela N Viaene, John C Greenwood, Frances S Shofer, Johannes K Ehinger, Shih-Han Kao, Todd J Kilbaugh.

   BACKGROUND: Organophosphate (OP) compounds are widely used agricultural chemicals that pose significant public health and chemical threat concerns due to their neurotoxic effects. Although OP toxicity has classically been attributed to acetylcholinesterase inhibition and cholinergic crisis, emerging evidence suggests mitochondrial dysfunction may represent an additional and clinically relevant mechanism of injury. Experimental OP exposure has been associated with impaired electron transport chain activity, reduced ATP production, increased oxidative stress, and disruption of mitochondrial membrane integrity. However, there are currently no established mitochondrial-targeted therapies for OP poisoning. Diisopropyl fluorophosphate (DFP), a well-established OP surrogate, reproduces several neurologic and mitochondrial features of nerve agent exposure. Cyclosporine A (CsA), an inhibitor of the mitochondrial permeability transition pore (mPTP), may represent a potential mitochondrial-targeted intervention.
METHODS: This preliminary translational study employed both in vitro and in vivo models to evaluate mitochondrial respiratory dysfunction following acute DFP exposure and to explore the feasibility of mitochondrial-targeted treatment paradigms using CsA. Human donor-derived peripheral blood mononuclear cells (PBMCs) were used for DFP and CsA dose-finding and mitochondrial respiratory characterization using high-resolution respirometry (Oroboros O2k) with standardized substrate-uncoupler-inhibitor titration (SUIT) protocols. In parallel, a non-survivor Sprague-Dawley rat model of acute DFP exposure was developed incorporating invasive hemodynamic monitoring, controlled ventilation, venous blood gas analysis, and CsA treatment paradigms administered either following DFP exposure or as pretreatment prior to exposure. Brain cortical homogenates were prepared for ex vivo respiratory assessment.
RESULTS: Preliminary findings demonstrated that DFP exposure was descriptively associated with impaired mitochondrial respiration across multiple oxidative phosphorylation (OXPHOS)- and electron transport system (ETS)-linked respiratory states in both PBMC and rodent models. DFP exposure was additionally associated with physiologic and metabolic derangements, including acidosis and elevated lactate concentrations. Post-DFP CsA administration was associated with partial preservation of mitochondrial respiration across several respiratory states, while the Pre-DFP CsA group demonstrated respiratory profiles more closely approximating control values in select OXPHOS- and ETS-linked states, accompanied by relatively preserved physiologic and metabolic parameters.
CONCLUSIONS: These preliminary findings support the feasibility of integrating mitochondrial respiratory phenotyping into translational models of acute OP toxicity and further support investigation of mitochondrial-targeted strategies in OP-associated mitochondrial dysfunction. The observed respiratory and physiologic trends associated with CsA exposure, particularly in the pretreatment paradigm, provide an exploratory foundation for future preclinical studies evaluating mitochondrial-directed countermeasures in OP poisoning.

Keywords:  Cyclosporine A ; Diisopropyl fluorophosphate (DFP) ; High-resolution respirometry; Mitochondrial dysfunction; Mitochondrial permeability transition pore (mPTP); Organophosphate poisoning

DOI:  https://doi.org/10.1007/s13181-026-01144-6
Toxicol Appl Pharmacol. 2026 Aug 19. pii: S0041-008X(26)00293-0. [Epub ahead of print] 117997

Mitochondrial sensitivity to Ca2+-induced permeability transition in mouse liver exhibits time-of-day dependence.

Tomoyuki Sato, Kohei Yamaguchi, Taira Wada, Shigeki Shimba, Tomoki Abe, Yukiko Tanigawa, Katsutaka Oishi.

  Mitochondrial permeability transition (MPT) is a loss of mitochondrial inner membrane integrity following opening of the MPT pore in the mitochondrial inner membrane that can lead to cell death. Whether hepatic MPT sensitivity fluctuates across the day remains unclear. Here, we examined time-of-day regulation of mitochondrial sensitivity to MPT in mouse liver. We found that MPT sensitivity of hepatic mitochondria fluctuates across the day with a peak near the end of the light (inactive) phase and a trough near the end of the dark (active) phase. Restricting the feeding time window to the active or inactive phase shifted the phase of this rhythm, indicating that feeding rhythm strongly contributes to the fluctuation of MPT sensitivity. This fluctuation in MPT sensitivity was inversely correlated with mitochondrial glutathione levels. To examine the involvement of the circadian clock in these fluctuations, we compared these fluctuations between hepatocyte-specific Bmal1 knockout mice (Bmal1-LKO) and their littermates. In Bmal1-LKO, the circadian fluctuation of MPT sensitivity and mitochondrial glutathione levels were attenuated. Moreover, time-of-day differences in ischemia/reperfusion-associated MPT and liver injury were altered in Bmal1-LKO. Collectively, these findings suggest that feeding rhythms and hepatocyte Bmal1 are involved in shaping time-of-day-dependent MPT sensitivity, in part through oscillation of the mitochondrial glutathione pool, thereby influencing early susceptibility to ischemia/reperfusion injury. These findings demonstrate that mitochondrial sensitivity to MPT represents a temporally regulated toxicological threshold in the liver, which may influence early vulnerability to hepatic injury.

Keywords:  Circadian rhythm; Ischemia-reperfusion injury; Liver; Mitochondrial injury

DOI:  https://doi.org/10.1016/j.taap.2026.117997
iScience. 2026 Aug 21. 29(8): 116955

Specialized cortical ER architecture modulates Ca2+ signaling dynamics.

Raphael J Courjaret, Lloyd Lee, Hana Mohamed, Fang Yu, Lama Assaf, Melanie Fisher, David I Yule, Mark Terasaki, James Sneyd, Khaled Machaca.

  Ca2+ signaling is ubiquitous and supports a multitude of cellular events. Specificity in Ca2+ signaling is encoded in its spatial and temporal dynamics. Ca2+ tunneling regulates the dynamics of Ca2+ signals downstream of store operated Ca2+ entry (SOCE). Here, we describe a novel cortical ER (cER) architectural feature, that we call the cER-basket, which underpins Ca2+ tunneling. We discovered the cER-basket through a combination of 3D reconstructions of the cortical ER at the ultrastructural level coupled to mathematical modeling of Ca2+ tunneling. Using insights from the modeling to inform experimental approaches and vice versa, we show that the detailed structural features of the cER-basket support Ca2+ tunneling. Therefore, we report a specific cortical ER structure, the cER-basket, which modulates cellular Ca2+ dynamics.

Keywords:  ER structure; calcium signaling; calcium tunneling; mathematical modeling; store-operated calcium entry

DOI:  https://doi.org/10.1016/j.isci.2026.116955
Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2606216123

Repression of ferroptotic cell death mediated antitumor immunity by mitochondrial calcium signaling.

Jianwen Chen, Bao Zhao, Hong Dong, Zhiwei Liao, Shen Wang, Anjun Ma, Yajun Sun, Xiang Cheng, Shengyin Lin, Xinghui Li, Gang Xin, Kai He, Bei Liu, Yu L Lei, Qin Ma, Kymberly M Gowdy, Ruili Xie, Xiaolin Cheng, Zihai Li, Haitao Wen.

  Ferroptosis is a unique type of programmed cell death caused by excessive lipid peroxidation and represents a vulnerability in certain types of cancer. However, the signaling mechanisms that modulate ferroptosis and its functional consequence on the tumor microenvironment are poorly understood. Here, we demonstrate an inhibitory effect of mitochondrial calcium uniporter (MCU) on ferroptosis during embryogenesis and tumor development. MCU-dependent production of metabolite acetyl-coenzyme A (acetyl-CoA) supports the normal function of glutathione peroxidase 4 (GPX4), a critical gatekeeper of ferroptosis. Mechanistically, acetylation of GPX4 on lysine 90 (K90) prevents the formation of a detrimental salt bridge between K90 and aspartate 23, therefore protecting GPX4 enzymatic activity and avoiding ferroptosis. Deletion of MCU in cancer cells caused a robust antitumor T cell response and significantly blunted tumor growth. Thus, our findings indicate MCU-mediated acetyl-CoA metabolism as a critical anti-ferroptosis mechanism, which can be investigated as potential therapeutic candidate for tumor treatment.

Keywords:  GPX4; MCU; ferroptotic cell death

DOI:  https://doi.org/10.1073/pnas.2606216123
Apoptosis. 2026 Aug 20. pii: 209. [Epub ahead of print]31(9):

Programmed cell death in kidney disease: integrated crosstalk among ferroptosis, pyroptosis, apoptosis, and cuproptosis.

Jiajun Sang, Zhentao Guo, Chengxia Kan, Fang Han, Xiaodong Sun, Kexin Zhang.

  Programmed cell death (PCD) is a central determinant of kidney injury, maladaptive repair, and chronic progression. Beyond classical apoptosis, the identification of ferroptosis, pyroptosis, and cuproptosis has expanded the conceptual framework of renal pathophysiology by linking cell fate decisions to redox imbalance, inflammatory signaling, mitochondrial metabolism, and metal ion homeostasis. Ferroptosis is driven by iron-dependent phospholipid peroxidation and impaired antioxidant defenses; pyroptosis is mediated by inflammasome activation, gasdermin pore formation, and cytokine release; apoptosis results from caspase-dependent cellular dismantling; and cuproptosis reflects copper-induced disruption of lipoylated tricarboxylic acid cycle proteins and mitochondrial proteostasis. Here, we propose a "metabolic crisis-cascade" framework, in which progressive disruption of energy metabolism, redox balance, and metal homeostasis acts as a unifying upstream mechanism linking multiple PCD pathways during kidney injury. In acute kidney injury (AKI), ferroptosis and pyroptosis contribute prominently to early tubular injury, whereas persistent apoptosis, recurrent ferroptotic stress, and emerging copper-dependent metabolic vulnerability contribute to chronic kidney disease (CKD), diabetic kidney disease, glomerular injury, inflammation, and fibrosis. These pathways are interconnected through common stress signals, including reactive oxygen species accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, Nrf2/Keap1-dependent antioxidant responses, inflammasome activation, and metal dysregulation. Understanding their temporal and compartment-specific activation is essential for distinguishing adaptive responses from irreversible damage. Targeting lipid peroxidation, inflammasome signaling, mitochondrial stability, apoptosis regulation, and copper metabolism may provide complementary strategies for limiting renal injury and preventing AKI-to-CKD transition. Future studies integrating multiomics approaches and disease-stage-resolved models will be required to define actionable cell-death signatures and enable precision interventions in kidney disease.

Keywords:  Apoptosis; Cuproptosis; Ferroptosis; Kidney disease; Pyroptosis

DOI:  https://doi.org/10.1007/s10495-026-02428-6
Microbiol Spectr. 2026 Aug 18. e0153726

Iron-responsive transcription factor SreA regulates calcium homeostasis independently of calcineurin-Crz1 pathway in Fusarium graminearum.

Heeji Moon, Jiyeun Park, Soobin Shin, Sieun Kim, Jung-Eun Kim, Hokyoung Son.

  Calcium is an abundant intracellular ion that is intricately involved in various cellular processes. The precise regulation of calcium homeostasis is critical for fungal physiology. In fungi, calcium signaling is primarily mediated by the calmodulin-calcineurin pathway, with the transcription factor Crz1 acting as a key downstream regulator of calcium homeostasis. However, other transcription factors that contribute to calcium homeostasis in Fusarium graminearum are yet to be systematically identified. Here, we screened 675 transcription factor deletion mutants of F. graminearum under calcium stress and identified eight mutants, including crz1 and sreA. We found that SreA, a known iron homeostasis regulator, is required for calcium stress tolerance, separate from its role in iron homeostasis. Furthermore, SreA functions independently of the calcineurin-Crz1 pathway, and deletion of SREA alters cytosolic Ca2+ dynamics following calcium stimulation. Our findings highlight a previously unrecognized role of SreA in fungal calcium homeostasis and suggest that SreA contributes to calcium stress response by maintaining appropriate cytosolic Ca2+ signaling in F. graminearum.IMPORTANCECalcium regulation is vital for the survival and pathogenicity of fungi. While the transcription factor Crz1 is widely recognized as the main regulator of calcium homeostasis, this study reveals that another transcription factor, SreA, plays a critical and previously unrecognized role in Fusarium graminearum. Although SreA is a well-established regulator of iron homeostasis, it also plays a critical role in calcium stress tolerance. This function is independent of both iron homeostasis and the canonical calcineurin-Crz1 pathway. Together, these findings broaden our understanding of the transcriptional regulators involved in fungal calcium homeostasis.

Keywords:  Fusarium graminearum; calcium homeostasis; iron homeostasis; transcription factor

DOI:  https://doi.org/10.1128/spectrum.01537-26